Arsenical compound.



erties occurs which a NITED- STATES PATENT OFFICE.

WALTER AJIJACOBS, OEMOUNT VERNON, AND WADE H. BROWN, MIGHA'EL HEIDEL- PEARCE, OF NEW YORK, N. Y., ASSIGNORS TO THE ROCKE- E FOR MEDICAL RESEARCH OF NEW TION DIE NEW YORK. YORK, N. Y., A CORPORA- AIBSENICAL COMPOUND.

1,280,124 Specification of Letters fatent. Patented S pt. 24 1918 Ho Drawing. Original application filed October 8, 1917, Serial No. 194,459. Divided and this application filed January 16, 1918. Serial No. 212,116.

' To all whom it may concern: increase in the curative ower Be it known that we, WALTER A. JACOBS, arsenical compound in @115 treatnllfn t d? Ph. D., residing atMount Vernon, Westchesinfections. We have found in eneral that ter county New York, Wane H. Bnowx, substances of this type, which ar e character 55 M. D yreslding atFlushmg, in the city of ized by the possession of a glvcinamid or New ork, borough of Queens, county of RNHDPLCONH, group (R. as seen below Queens, Neyv 1 01l Mlcnann HEIDELBERGER, referring to aromatic arsonic acid in gen Ph. D, residing 111 the city. of New York, eral), are powerful therapeutic agents borough of Manhattan, county and State of Thus, we have found that similar results are 60 lTeW Y0rk, and LGUISE PEATROE, M. D., residobtained by the use of the homolo ues of the mg in the city of New Xork, borough of above substance, such as the N-thlylglycin- Manhattan, county and State of New York, amid-p-arsonic acids,andN-xylvlglycinamidall citizens of the United States, have jointly p-arsonic acids. and also of the isomers of invented a new and Improved Arsenical these substances in which them-sonic acid or 86 Compound,-of vyhich the following is a speci- AsO H radical is situated in the ortho or fication, thiszbeing a division of our applicameta position to the glycinamid group. \Ve tion, Serial No. 194 ,4539, filed October 3,1917. have also fou'nd that other compounds be- \Ve have found,1nthe course of our chemilonging to the new tvpe of therapeutica-llt cal and biological researches that, whereas valuable arsenicals. are obtained when the 70 the Well-known substance chemically desigglycinamid or aminoacet'aniid radical is nated as Nphenylglyc1n-p-arsonic acid corchanged to homologues such as the cat-aminoresponding t the following formula and depropionamids, 1 I

scribed in D. R. P. 204r66e /O o AS 01 76 p .03 \OH I v l so l 5 a i H.CH.GQNH, f a a I, I a VII-701110001! r is 0 little therapeutic value in the treatment of trypanosomahor',spirochaetal infections, 01 the ammophenylmetamlds a5 whenthe CO OH group of this compound is transformettun.v the manner to be described belowantq the carbonamid or CONE, group, v 011 result ng 1n a compound which may be des-' ignated as N-phenylglycinamid-p-arsonic acid corresponding the following fora a mule:

' ILOECONH,

Ai-OH a on.*'\. l l t lnwhich, as in the above-mentioned substances, the a-amino group isjoined; tothe x" phenyl-p-arsonic acid residuebr} itshomolo' 'ucs-or isomers' M j 1; f "if l 7 'f. v lVehave further found'that by replacing -ze u in the above-ljn'entioned substances one or 1150 a remarkable change in thebiological p op both of the hydrogens of the amid group by 's'sheun t ene striking 1 an alkyl as shownin the fOllOWIDgl fOImUlw,

where R may be methyl ethyl propyl or benzyl or substituted benz yl that this general type of therapeutically important substances are still further extended.

As arsonic acids, all the above-described substances are readil soluble in the equivalent amounts of alliali or alkali carbonates, and when, so treated form neutral and stable solutions of their salts. v Substances of the types above described were obtained in two ways:

1. By the interaction of the corresponding aminophenyl arsonic acid, or preferably its salt, in aqueous or in dilute alcoholic or acetone solution with the corresponding a-halogenacylamid, and when necessary with a hydriodic acid salt, as a catalyzer.

2. the reaction of the phenylglycin ester arsonic acid with ammonia or an amin, or by any of the other usual methods for converting the COOH group into the CONR group, where R is hydrogen or e shall now describe the preferred methods for the preparation of these substances.

Ewample- I .-N -Phenylglycin amidp -arsonic acid.

' 217 grams of p-aminophenylarsonic acid are dissolved in one liter of normal sodium or potassium h droxid solution. 187 grams.

of chloracetamid (or the equivalent amount of bromo or iodo acetamid) are added. and the mixtureboiled under a reflux for onehalf to one hour. The clear solution on cooling deposits a copious mass of lustrous crystals of the crude ,phenylglycinamid-p arsonic acid. Concentrated hydrochloric acid is then added until the mixture becomes distinctly acid to Kongo red." The mixture is then filtered and" the residue thoroughly .washed with cold water. For purification this product is then suspended in several parts of water and sodiu'mhydroxid, or other alkali added until solution is complete. The

salts.

solution is then filtered and treated with an excess of acetic acid, which precipitates the free acid in pure form. Upon filtering and careful washing and dryin of the residue a pure stable product is o tained. In the above reaction the alkaline hydro'xid may be substituted by any other suitable basic substance.

This new product with the following formula parts of water and, while stirring the mixture, sodium hydroxid solution is carefully added until solution of the acid is complete and the reaction of the solution is neutral to litmus. Several volumes of 95 per cent. alcohol are then added While stirring the mixture. The sodium salt separate-s as a color less lustrous crystalline substance. By filterin the-mixture; washing the residue with a litt e 85 per. cent. alcohol and drying it in the air, a stable salt containing approximately one-half molecule of water of crystallization is obtained. This salt is extremely soluble in water 'forining neutral solutions and it is therefore especially suitable for therapeutic use. By the substitution of potassium hydroxid or ammonia the corresponding. salts can be made by the above process.

Example- 11. N phenylgl cin -*p arsonic acid methyl ester of the to lowing formula .CH OOOCH,

ess:

A of 10 parts phenylglycin-p-a'ris readilyohtainable by the following procsonic acid 90 ms ofdry many: aLwhOI and 3 parts concentrated sulfuric. acid ewe:- separates as micros am boiled under areflux for two hours, who

ic needles, dll-utin it i with ut 270 eoolinglthe and .Thisester decomposes at a with prelimina softening. One-part of t e methyl ester is carefully added to three parts of concentrated ammonia water while the mixture is being stirred chilled. LA thick mass ofcrystals of the ammonium salt is first obtained which,

' after a short while, dissolves to a clear solution, as; the reaction proceeds. After twentyfour hours the excess ammonia is removed preferably-in vacuo, and the residue. diluted with water. added, which precipitates the phenylglyc- An excess of acetic acid is then inamid-p-arsomc acid in the pure characteristic form described inExample I. In Example II the homologous esters, such as the ethyl ester, can be used. The sodium saltis preparedas in Example I.

E a III.N- PhenyZ-p-arsmn'cncz'd)- a-pheny glycine amid.

8 grams of p-aminophenylarsonic acid are dissolvedin 400 cc. normal sodium hydi-oxid solution, and 68 grams phenylchloro acetamid and 500 cc. 95 percent. alcohol are added. To facilitate the reaction grams of sodium iodid are then added and the mix ture is heated under a reflux for several hours. Qn cooling the mixture the reaction product crystallizes out. This, after filtration, purified by redissolving itin dilute alkali or ammonia and reprecipitating it with. acid. For conversion into the sodium salt, this is suspended in a small amount of wa'ter'and sodium hydroxid added until solotion is complete. This solution, which should be neutral to litmus, is then treated with sodium acetate to salt out the sodium salt. Forfinal purification the salt is re crystallized from per cent. alcohol, from which it separates with ap roximately 4 molecules of water. of crysta lization. The

a salt is stable and dissolves easily in water.

. The foregoing are a few examples of substances falling within the spint and scope of our invention. It will be obvious to any one skilled in the art that many variations in the exact constitution of the substances described ma 0 from the spirlt and scope of our invent on.

' which R is an a be made without departing i What we claim is:

As a. new. product, a soluble salt of an aromatic arsonic acid having in its molecule an a-aminoacylamin side chain, the aromatic nucleus being joined to the a-amino group in said side chain, the acyl radical of said- .side chain conta' a plurality of carbon atoms.

2. As a new product, a soluble salt of an, aromatic arsenic acid havingain its molecule an c-amlnoacylamin side c in having the general formula -NH.GHR.CONB'R in l or aryl or hydro and R andtR'. are a lot hydrogen, aromatic nucleus bein joined to the a-amino group in said side c ain.

3. As a new product, a'soluble salt of an aromatic arsenic acid having in its molecule the glycinamid group NH.CH,.CONH,,

attached to the aromatic nucleus as a side chain, the aromatic nucleus be' joined to the wamino group in the said ifie chain.

4. Asa new product, a soluble salt ofan v N-phenylglycin-amid arsenic acid.

5. As a new product, a soluble salt of N-phenylglycin-amid-p-arsonic acid.

6. a As a new product, the sodium salt of an aromatic arsenic acid having in itsmolecule an a-aminoacylamin side chain, the aromatic nucleusbeing jOlIlBd to the e-ammo group 1n said side ChalI'i. the acyl radical ofsaid side chain containing a plurality of carbon atoms. e

7. Asa new product, the sodium salt of an aromatic arsenic acidhaving inits mole cule an oc eminoacylamin side chainha the general formula --NH.CHR.GONR'R in. which R- is an alkyl or aryl or hydrogen and R and R are alkyl or hydrogen, the

aromatic nucleus'being joinedto the c-amino group in said slde chain. e e

8. As a new product, the sodmmsalt of an aromatic arsenic acid having in its molecule the glycinamid group -NH.CH .CONT(II,, attached to the aromatic nucleus asa si e chain, the aromatic nucleus joined to' the os-amino group in thesaid si e 9. As a new product, the sodium salt of an N henyIglycin-amid arsonic acid. 

